Unlike other tissues which can survive extended periods of hypoxia, brain tissue is particularly sensitive to deprivation of oxygen or energy. Permanent damage to neurons can occur during brief periods of hypoxia, anoxia or ischemia. Neurotoxic injury is known to be caused or accelerated by certain excitatory amino acids (EAA) found naturally in the central nervous system (CNS). Glutamate (Glu) is an endogenous amino acid which has been characterized as a fast excitatory transmitter in the mammalian brain. Glutamate is also known as a powerful neurotoxin capable of killing CNS neurons under certain pathological conditions which accompany stroke and cardiac arrest. Normal glutamate concentrations are maintained within brain tissue by energy-consuming transport systems. Under low energy conditions which occur during conditions of hypoglycemia, hypoxia or ischemia, cells can release glutamate. Under such low energy conditions the cell is not able to take glutamate back into the cell. Initial glutamate release stimulates further release of glutamate which results in an extracellular glutamate accumulation and a cascade of neurotoxic injury.
It has been shown that the sensitivity of central neurons to hypoxia and ischemia can be reduced by either blockage of synaptic transmission or by the specific antagonism of postsynaptic glutamate receptors [see S. M. Rothman and J. W. Olney, "Glutamate and the Pathophysiology of Hypoxia--Ischemic Brain Damage," Annals of Neurology, Vol. 19, No. 2 (1986)]. Glutamate is characterized as a broad spectrum agonist having activity at three neuronal excitatory amino acid receptor sites. These receptor sites are named after the amino acids which selectively excite them, namely: Kainate (KA), N-methyl-D-aspartate (NMDA or NMA) and quisqualate (QUIS).
Neurons which have EAA receptors on their dendritic or somal surfaces undergo acute excitotoxic degeneration when these receptors are excessively activated by glutamate. Thus, agents which selectively block or antagonize the action of glutamate at the EAA synaptic receptors of central neurons can prevent neurotoxic injury associated with anoxia, hypoxia or ischemia caused by stroke, cardiac arrest or perinatal asphyxia.
Aminophosphonic acids have been investigated as neurotransmitter blockers [see M. N. Perkins et al, Neuroscience Lett., 23, 333 (1981); and J. Davies et al, Neuroscience Lett., 21, 77 (1981)]. In particular, compounds such as 2-amino-4-(2-phosphonomethylphenyl)butyric acid and 2-(2-amino-2-carboxy)ethylphenylphosphonic acid have been synthesized for evaluation as antagonists in blocking the action of the neurotransmitter compounds L-glutamic acid and L-aspartic acid [K. Matoba et al, "Structural Modification of Bioactive Compounds II. Syntheses of Aminophosphonic Acids", Chem. Pharm. Bull., 32, (10) 3918-3925 (1984)].
Intact hippocampal structure is necessary for the brain to process information and store it in memory. The phenomenon of "long term potentiation" (LTP) may be the mechanism by which this process occurs. The leading role of NMDA receptors, a sub-type of excitatory amino acid receptor, in LTP has been firmly established by electrophysiological studies. NMDA antagonists such as 2-amino-7-phosphonoheptanoic acid (APH) may inhibit the induction of LTP.
Certain cyclopropyl-substituted amino acids have been isolated from natural plant sources. For example, cis-.alpha.-(carboxycyclopropyl)glycine and trans-.alpha.-(carboxycyclopropyl)glycine were obtained, respectively, from the seed of Aesculus and Blighia, the cis-isomer having been characterized as a potent inhibitor of mungbean seedling growth [L. Fowden et al, Phytochemistry, 8, 437-443 (1969)].
Japanese Patent Application No. 154,499, published on Feb. 17, 1986, describes a series of cyclopropylglycine derivatives for use in foodstuffs, agrochemicals or pharmaceuticals. Certain 3,4-cyclopropylglutamate isomers have been evaluated in an electrophysiology assay involving a periodically oscillating neuron of an African giant snail [K. Yamanoi et al, Tetrahedron Letters, 29, 1181-1186 (1988)].
NMDA receptor agonists have been described. For example, trans- and cis-3,4-cyclopropyl glutamates have been evaluated in glutamate subclass receptor binding assays for displacement of radiolabelled L-glutamate, kainate and AMPA, wherein the cis-isomer was found to be an agonist producing changes similar to L-glutamate [6th Camerino-Noordwijkerhout Symposium: Recent Advances in Receptor Chemistry, Abstracts, Camerino, Italy, 73-74 (Sept. 1987)].